ABSTRACT
RATIONALE: The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1ß (IL-1ß) release and activation. IL-1ß amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1ß in bronchiectasis has not been investigated. OBJECTIVES: To characterise the role of airway IL-1ß in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity. METHODS: Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1ß was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1ß in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air-liquid interface culture were used to study the effect of IL-1ß on cilia function. RESULTS: Patients with high sputum IL-1ß had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1ß. The active-dominant form of IL-1ß was associated with increased disease severity. High IL-1ß was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1ß treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro. CONCLUSIONS: A subset of stable bronchiectasis patients show increased airway IL-1ß, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.
Subject(s)
Bronchiectasis , Interleukin-1beta , Mucociliary Clearance , Severity of Illness Index , Sputum , Humans , Interleukin-1beta/metabolism , Bronchiectasis/physiopathology , Bronchiectasis/metabolism , Bronchiectasis/microbiology , Female , Male , Middle Aged , Sputum/metabolism , Aged , Inflammasomes/metabolism , Mucus/metabolism , Caspase 1/metabolism , Microbiota , Inflammation , Cohort Studies , RNA, Ribosomal, 16S/genetics , Adult , Cilia/metabolismABSTRACT
Bronchiectasis is a complex and heterogeneous inflammatory chronic respiratory disease with an unknown cause in around 30-40% of patients. The presence of airway infection together with chronic inflammation, airway mucociliary dysfunction and lung damage are key components of the vicious vortex model that better describes its pathophysiology. Although bronchiectasis research has significantly increased over the past years and different endotypes have been identified, there are still major gaps in the understanding of the pathophysiology. Genomic approaches may help to identify new endotypes, as has been shown in other chronic airway diseases, such as COPD.Different studies have started to work in this direction, and significant contributions to the understanding of the microbiome and proteome diversity have been made in bronchiectasis in recent years. However, the systematic application of omics approaches to identify new molecular insights into the pathophysiology of bronchiectasis (endotypes) is still limited compared with other respiratory diseases.Given the complexity and diversity of these technologies, this review describes the key components of the pathophysiology of bronchiectasis and how genomics can be applied to increase our knowledge, including the study of new techniques such as proteomics, metabolomics and epigenomics. Furthermore, we propose that the novel concept of trained innate immunity, which is driven by microbiome exposures leading to epigenetic modifications, can complement our current understanding of the vicious vortex. Finally, we discuss the challenges, opportunities and implications of genomics application in clinical practice for better patient stratification into new therapies.
Subject(s)
Bronchiectasis , Genetic Predisposition to Disease , Genomics , Lung , Bronchiectasis/physiopathology , Bronchiectasis/genetics , Bronchiectasis/metabolism , Bronchiectasis/immunology , Humans , Lung/physiopathology , Lung/microbiology , Lung/metabolism , Microbiota , Host-Pathogen Interactions , Phenotype , Proteomics , Epigenesis, Genetic , Immunity, Innate , Animals , Risk Factors , Metabolomics , Prognosis , EpigenomicsABSTRACT
o presente trabalho tem como objetivo a revisão dos principais tópicos relativos à bronquiectasia,desde o conceito até o tratamento,enfocando etiologia,patogenia,tipos,manifestações clinicas,diagnóstico,tratamento,complicações e prognóstico